Anterograde Axonal Transport in Neuronal Homeostasis and Disease

Guillaud, Laurent; El-Agamy, Sara Emad; Otsuki, Miki; Terenzio, Marco

doi:10.3389/fnmol.2020.556175

Cited by 75 publications

(58 citation statements)

References 253 publications

(294 reference statements)

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“…Microtubules form a broad cytoskeletal network and are known to provide cargo transport functions throughout the cell, including trafficking of mRNA for cytosolic proteins [ 8 , 18 , 21 ]. To examine their role in trafficking membrane protein mRNA, we tested the effects of a microtubule inhibitor (colchicine; 10 µM; 8 and 24 h) on the cellular distribution of mRNA.…”

Section: Resultsmentioning

confidence: 99%

Distributed synthesis of sarcolemmal and sarcoplasmic reticulum membrane proteins in cardiac myocytes

et al. 2021

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It is widely assumed that synthesis of membrane proteins, particularly in the heart, follows the classical secretory pathway with mRNA translation occurring in perinuclear regions followed by protein trafficking to sites of deployment. However, this view is based on studies conducted in less-specialized cells, and has not been experimentally addressed in cardiac myocytes. Therefore, we undertook direct experimental investigation of protein synthesis in cardiac tissue and isolated myocytes using single-molecule visualization techniques and a novel proximity-ligated in situ hybridization approach for visualizing ribosome-associated mRNA molecules for a specific protein species, indicative of translation sites. We identify here, for the first time, that the molecular machinery for membrane protein synthesis occurs throughout the cardiac myocyte, and enables distributed synthesis of membrane proteins within sub-cellular niches where the synthesized protein functions using local mRNA pools trafficked, in part, by microtubules. We also observed cell-wide distribution of membrane protein mRNA in myocardial tissue from both non-failing and hypertrophied (failing) human hearts, demonstrating an evolutionarily conserved distributed mechanism from mouse to human. Our results identify previously unanticipated aspects of local control of cardiac myocyte biology and highlight local protein synthesis in cardiac myocytes as an important potential determinant of the heart’s biology in health and disease.

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Section: Resultsmentioning

confidence: 99%

Distributed synthesis of sarcolemmal and sarcoplasmic reticulum membrane proteins in cardiac myocytes

et al. 2021

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“…As part of the neuronal cytoskeleton, neurofilaments, microtubules, and associated proteins not only maintain cellular stability but also impact on critical neuronal functions, such as the regulation of axonal caliber [1][2][3], conduction velocity [4], axonal transport [5][6][7], and synaptic function [8]. Therefore, it is not surprising that these elements play crucial roles in the pathogenesis of a variety of central nervous system disorders [9][10][11].…”

Section: Introductionmentioning

confidence: 99%

The Cytoskeletal Elements MAP2 and NF-L Show Substantial Alterations in Different Stroke Models While Elevated Serum Levels Highlight Especially MAP2 as a Sensitive Biomarker in Stroke Patients

et al. 2021

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In the setting of ischemic stroke, the neurofilament subunit NF-L and the microtubule-associated protein MAP2 have proven to be exceptionally ischemia-sensitive elements of the neuronal cytoskeleton. Since alterations of the cytoskeleton have been linked to the transition from reversible to irreversible tissue damage, the present study investigates underlying time- and region-specific alterations of NF-L and MAP2 in different animal models of focal cerebral ischemia. Although NF-L is increasingly established as a clinical stroke biomarker, MAP2 serum measurements after stroke are still lacking. Therefore, the present study further compares serum levels of MAP2 with NF-L in stroke patients. In the applied animal models, MAP2-related immunofluorescence intensities were decreased in ischemic areas, whereas the abundance of NF-L degradation products accounted for an increase of NF-L-related immunofluorescence intensity. Accordingly, Western blot analyses of ischemic areas revealed decreased protein levels of both MAP2 and NF-L. The cytoskeletal alterations are further reflected at an ultrastructural level as indicated by a significant reduction of detectable neurofilaments in cortical axons of ischemia-affected areas. Moreover, atomic force microscopy measurements confirmed altered mechanical properties as indicated by a decreased elastic strength in ischemia-affected tissue. In addition to the results from the animal models, stroke patients exhibited significantly elevated serum levels of MAP2, which increased with infarct size, whereas serum levels of NF-L did not differ significantly. Thus, MAP2 appears to be a more sensitive stroke biomarker than NF-L, especially for early neuronal damage. This perspective is strengthened by the results from the animal models, showing MAP2-related alterations at earlier time points compared to NF-L. The profound ischemia-induced alterations further qualify both cytoskeletal elements as promising targets for neuroprotective therapies.

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“…Furthermore, previously mentioned STAU2 and ELAVL4 both participate in kinesinmediated transport of mRNAs from the nucleus to neurites (Bronicki and Jasmin 2013;Tang et al 2001). Anterograde transport of mitochondria and mRNA via kinesins is crucial for synapse health, learning, and memory, and disruptions of this process are associated with several neurodegenerative disorders (Guillaud et al 2020). Disruption of mitochondrial transport in neurons also impairs mitochondrial homeostasis, which has been suggested to play a central role in many neurodegenerative disorders (Sheng and Cai 2012).…”

Section: Discussionmentioning

confidence: 99%

“…See Table 2 for column descriptions. A majority of shared downregulated orthologs are involved in one or more of the following processes: cellular cargo transport, endo/exocytosis, proteostasis, lipid metabolism, energy metabolism, mitochondrial homeostasis, and signaling synapse in response to synaptic activity is also central to synapse function and health (Guillaud et al 2020;Hafezparast et al 2003).…”

Section: Discussionmentioning

confidence: 99%

Aplysia Neurons as a Model of Alzheimer’s Disease: Shared Genes and Differential Expression

Kron

Fieber

2021

J Mol Neurosci

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Although Alzheimer’s disease (AD) is the most common form of dementia in the United States, development of therapeutics has proven difficult. Invertebrate alternatives to current mammalian AD models have been successfully employed to study the etiology of the molecular hallmarks of AD. The marine snail Aplysia californica offers a unique and underutilized system in which to study the physiological, behavioral, and molecular impacts of AD. Mapping of the Aplysia proteome to humans and cross-referencing with two databases of genes of interest in AD research identified 898 potential orthologs of interest in Aplysia. Included among these orthologs were alpha, beta and gamma secretases, amyloid-beta, and tau. Comparison of age-associated differential expression in Aplysia sensory neurons with that of late-onset AD in the frontal lobe identified 59 ortholog with concordant differential expression across data sets. The 21 concordantly upregulated genes suggested increased cellular stress and protein dyshomeostasis. The 47 concordantly downregulated genes included important components of diverse neuronal processes, including energy metabolism, mitochondrial homeostasis, synaptic signaling, Ca++ regulation, and cellular cargo transport. Compromised functions in these processes are known hallmarks of both human aging and AD, the ramifications of which are suggested to underpin cognitive declines in aging and neurodegenerative disease.

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Anterograde Axonal Transport in Neuronal Homeostasis and Disease

Cited by 75 publications

References 253 publications

Distributed synthesis of sarcolemmal and sarcoplasmic reticulum membrane proteins in cardiac myocytes

Distributed synthesis of sarcolemmal and sarcoplasmic reticulum membrane proteins in cardiac myocytes

The Cytoskeletal Elements MAP2 and NF-L Show Substantial Alterations in Different Stroke Models While Elevated Serum Levels Highlight Especially MAP2 as a Sensitive Biomarker in Stroke Patients

Aplysia Neurons as a Model of Alzheimer’s Disease: Shared Genes and Differential Expression

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